Clinical outcomes in susceptible isolates are best predicted by the peak serum level to MIC ratio. Serum drug levels are infrequently measured and are typically available only in the research setting [6]. Resistance to AMB is common in Aspergillus terreus, Pseudallescheria boydii complex, Scedosporium prolificans, Trichosporon spp., and Candida lusitaniae (Table 15.1). Resistance has been reported in other species and changes in ergosterol biosynthesis and/or the synthesis of alternative sterols is the proposed mechanism for reduced AMB activity in these isolates [7].

AMB is available in inhalational, oral, and intravenous formulations. The well-known nephrotoxicity seen with intravenous amphotericin B deoxycholate (AmBd; Fungizone) has prompted the development of lipid formulations with more favorable side-effect profiles so that in patients with hematological malignancies lipid formulations of AMB have largely replaced the use of AmBd. Liposomal amphotericin B (L-AMB; Ambisome), amphotericin B lipid complex (ABLC; Abelcet), and amphotericin B colloidal dispersion (ABCD; Amphotec, Amphocil) are all currently available lipid formulations with a high degree of protein binding (>95 %, primarily to albumin) and comparably long half-lives.

Cerebrospinal fluid levels are low (<5 % of concurrent serum concentration) yet AMB remains the drug of choice for cryptococcal meningitis [8]. Intrathecal AMB has been used in the salvage setting for both coccidioidal and candidal meningitis; however, this practice is seldom used due to poor patient tolerability, the difficulty of administration, and the availability of alternative agents.

Similarly, AMB has low vitreous penetration (0–38 %) and intraocular injections are often required in the treatment of deep-seated ophthalmologic fungal infections including candidal endophthalmitis [9, 10]. The route of elimination of AMB remains unknown and dosing need not be adjusted in patients with a reduced glomerular filtration rate.

The broad antifungal spectrum and experience with the use of amphotericin B accounts for its continued use despite toxicity concerns. Liposomal amphotericin B remains a recommended antifungal during the treatment of neutropenic fever following an open-label, randomized international trial comparing L-AMB to voriconazole [11]. A recent meta-analysis also suggests L-AMB is associated with lower mortality during empiric treatment of neutropenic fever [12].

AMB was previously the preferred first-line agent during the treatment of invasive aspergillosis; however, a comparative trial has now demonstrated a lower mortality rate when voriconazole is administered in this setting [13, 14]. AMB remains the agent of choice for treatment of mucormycosis and a delay in the prescribing of an AMB formulation in this population is associated with a twofold greater risk of death [15].

AMB in combination with flucytosine remains the drug of choice in the treatment of cryptococcal meningitis and in most cases a lipid formulation is preferred due to the decreased incidence of nephrotoxicity. Severe infection caused by one of the endemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis, and sporotrichosis) should also be treated with an AMB formulation.

Intravenous AmBd is typically given in doses of 0.7–1 mg/kg, while the lipid formulations are given in higher doses (3–5 mg/kg). Recently, in an attempt to define the efficacy of even higher doses of lipid formulations, doses of L-AmB (3 mg/kg vs 10 mg/kg) were given in a randomized trial of invasive mold infections. Success rates were similar in both arms although more nephrotoxicity was seen in those receiving higher L-AmB doses [16]. Despite these findings, in cases of severe or life-threatening disease, escalating doses of lipid AMB formulations may be indicated.

Local delivery of amphotericin B has been attempted through use of aerosolized therapy. Lipid preparations are preferred for inhalation and aerosolized delivery has been found effective in the prevention of pulmonary IFIs in lung transplantation and in bone marrow transplant recipients [17, 18].

Side effects of AmBd infusion include fever, chills, rigors, myalgias, bronchospasm, nausea and vomiting, tachycardia, tachypnea, and hypertension [19]. The use of lipid formulations has decreased the incidence of these untoward effects although ABCD has been associated with the development of dyspnea and hypoxia and L-AMB has been associated with back pain during infusion [9]. The potential nephrotoxicity of amphotericin B is well known and may occur in up to 30 % of patients. Vascular smooth muscle dysfunction with resultant vasoconstriction and ischemia are the presumed mechanism of renal injury following AMB administration [20]. Lipid preparations have lower rates of nephrotoxicity and studies have shown that when AmBd is replaced by a lipid formulation after the development of acute kidney injury, renal function stabilizes or improves in a significant proportion of patients [21]. Despite the higher drug costs of lipid AMB formulations, the reduction in hospital days when toxicity is avoided has proven the lipid formulations more cost-effective than AmBd [21].